1
(a) S. M. Hecht, Bleomycin: Chemical, Biochemical and Biological
structure of supercoiled DNA, two oxidation events that are close
in space are not necessarily close in terms of DNA sequence. When
the two strand breaks are too distant in the DNA sequence, the
hydrogen bonding network will prevent linearization of the DNA,
and, hence, only the formation of nicked DNA is observed. In
contrast, nicked DNA has a relaxed open circular structure, in
which there is a much greater probability that the two cleavage
events will take place in close proximity on opposite strands
compared to supercoiled DNA. As a result, direct double strand
cleavage by 3c is observed with nicked DNA." In this respect, the
behaviour of 3c differs from that of Fe–BLM, which effects double
strand cleavage of supercoiled DNA. In Fe–BLM, the two
oxidizing equivalents are delivered by a single iron complex, which
is proposed to hinge around the intercalating bithiazole moiety to
Aspects, Springer-Verlag, New York, 1979; (b) R. M. Burger, Chem.
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J. Chen and J. Stubbe, Nat. Rev. Cancer, 2005, 5, 102–112.
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C. A. Detmer, III and J. R. Bocarsly, J. Am. Chem. Soc., 1996, 118,
2
3
5
8
339–5345; (b) Y. Jin and J. A. Cowan, J. Am. Chem. Soc., 2005, 127,
408–8415. For hydrolytic double strand cleavage, see: (c) M. E. Branum,
A. K. Tipton, S. Zhu and L. Que, Jr., J. Am. Chem. Soc., 2001, 123,
898–1904.
1
4
5
D. Freifelder and B. Trumbo, Biopolymers, 1969, 7, 681–693.
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6
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Commun., 2005, 4578–4580; (f) M. Piti e´ , C. Boldron and G. Pratviel,
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Jr., Angew. Chem., Int. Ed. Engl., 1995, 34, 1512–1514; (b) G. Roelfes,
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Feringa, E. M u¨ nck and L. Que, Jr., Inorg. Chem., 2003, 42, 2639–2653.
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1d,e
cleave both DNA strands sequentially.
In conclusion, a new binuclear iron-based DNA cleaving
catalyst was developed by covalently linking two single strand
cleaving Fe–N4Py complexes. This biomimetic complex is capable
of effecting direct double strand cleavage activity. Following the
BLM design, our future efforts will focus on derivatives of 3c
containing a DNA intercalating moiety.
The authors thank Dr W. R. Browne and Dr R. M. Scheek for
useful discussion, and NRSC-Catalysis for financial support.
7
Notes and references
8
9
{
Although single strand cleavage will give rise to double strand breaks on
a statistical basis, it is important to note that single strand and direct double
strand cleavage represent different cleavage pathways.
Covalent linking of mononuclear copper complexes has resulted in very
selective DNA oxidation but not in double strand cleavage. See e.g.: (a)
K. J. Humphreys, K. D. Karlin and S. E. Rokita, J. Am. Chem. Soc.,
§
The first term of a Poisson distribution predicts that the amount of linear
11
DNA has a maximum around 37%. In practice this means that significant
amounts of a smear are produced in the gel, which makes quantitative
analysis impossible.
2002, 124, 6009–6019; (b) K. J. Humphreys, A. E. Johnson, K. D. Karlin
and S. E. Rokita, J. Biol. Inorg. Chem., 2002, 7, 835–842; (c) L. Li,
K. D. Karlin and S. E. Rokita, J. Am. Chem. Soc., 2005, 127, 520–521;
"
This does not exclude that other factors are involved as well. For
example, analogous to binuclear copper complexes, which recognize and
(d) T. Ito, S. Thyagarajan, K. D. Karlin and S. E. Rokita, Chem.
Commun., 2005, 4812–4814.
10 F. Mancin, P. Scrimin, P. Tecilla and U. Tonellato, Chem. Commun.,
2005, 2540–2548.
11 L. F. Povirk, W. W u¨ bker, W. K o¨ hnlein and F. Hutchinson, Nucleic
Acids Res., 1977, 4, 3573–3580.
9
cleave single strands of DNA extending from a junction, it is also
conceivable that 3c has greater affinity for nicks than 4. This would give
rise to an increased probability of a second single strand cut being
generated nearby, resulting in a double strand break.
1
82 | Chem. Commun., 2007, 180–182
This journal is ß The Royal Society of Chemistry 2007